Abstract Low-intensity pulsed ultrasound stimulation (LIPUS) is a promising technology for non-invasive deep brain neuromodulation. Unfortunately, this technology is presently not available in the clinic due to the lack of understanding of the molecular and cellular processes that take place in brain cells upon ultrasound stimulation. The goal of this project is to uncover these mechanism(s). Our preliminary data show that LIPUS elicit robust and consistent calcium signals in astrocytes, suggesting a totally unanticipated mechanism wherein the neuromodulatory effects of LIPUS are mediated by astrocytes, via direct or indirect activation of calcium channels. To investigate these hypotheses, we propose to dissect LIPUS-induced calcium signaling in astrocytes and neurons using pharmacological agents. If successful, this work will help make this new technology available to patients who currently do not have access to effective and safe therapeutic options. Non-invasive astrocyte stimulation with ultrasound may also lead to new treatments for traumatic brain injury, neurovascular diseases or dementia. In parallel to this effort, we will develop genetically-encoded fluorescent reporters of mechanical deformations of plasma membranes induced upon LIPUS. Our preliminary molecular engineering design is very promising and will lead to a patent application upon further characterization and optimization. These sensors will enable rapid and easy localization and quantification of physical perturbations produced in cells and tissues by exogenous and endogenous mechanical forces. We expect these reporters to have a major impact in mechanobiology and nanotechnology.